Understanding the Role of Genetics in Tumour and Cancer Biology

Abdulaziz Mohammed Asiri, Amer Al Ali, Mohammed H. Abu-Alghayth

Abstract


The interplay between genetics and cancer has been a focal point of research for decades, leading to profound understandings into the molecular mechanisms driving tumorigenesis. In this comprehensive review article, we explore the genetic basis of cancer, encompassing the diverse array of alterations that underline oncogenic transformation. From oncogenes to tumor suppressor genes, and from point mutations to chromosomal rearrangements, we delve into the molecular hallmarks of cancer and their implications for diagnosis, treatment, and prevention. Drawing on recent advancements in genomic technologies, we discuss the role of next-generation sequencing, single-cell sequencing, and computational modeling in unraveling the complexity of cancer genetics. Furthermore, we examine the clinical implications of genetic predisposition to cancer, highlighting the importance of genetic testing and counselling in cancer risk assessment and management. Through an exploration of tumor heterogeneity, clonal evolution, and therapeutic resistance, we underscore the challenges and opportunities in precision oncology. Finally, we discuss future directions in cancer genetics research, including precision prevention strategies and ethical considerations.

Keywords: Cancer Genetics; Oncogenes; Tumor Suppressor Genes; Genetic Alterations; Precision Oncology; Clonal Evolution   


Full Text:

PDF

References


Labi V, Erlacher M. How cell death shapes cancer. Cell death & disease, (2015); 6(3): e1675-e1675.

Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends-an update. Cancer epidemiology, biomarkers & prevention, (2016); 25(1): 16-27.

Więckiewicz G, Weber S, Florczyk I, Gorczyca P. Socioeconomic Burden of Psychiatric Cancer Patients: A Narrative Review. Cancers, (2024); 16(6): 1108.

Botezatu A, Iancu IV, Popa O, Plesa A, Manda D, Huica I, et al. Mechanisms of oncogene activation. New aspects in molecular and cellular mechanisms of human carcinogenesis, (2016); 9(1).

Joyce C, Rayi A, Kasi A. Tumor-suppressor genes. (2018).

Chen X, Agustinus AS, Li J, DiBona M, Bakhoum SF. Chromosomal instability as a driver of cancer progression. Nature Reviews Genetics, (2024); 1-16.

Reis AH, Vargas FR, Lemos B. Biomarkers of genome instability and cancer epigenetics. Tumor Biology, (2016); 37(10): 13029-13038.

Bashraheel SS, Domling A, Goda SK. Update on targeted cancer therapies, single or in combination, and their fine tuning for precision medicine. Biomedicine & Pharmacotherapy, (2020); 125: 110009.

Wade CA, Kyprianou N. Profiling prostate cancer therapeutic resistance. International journal of molecular sciences, (2018); 19(3): 904.

Kensler TW, Spira A, Garber JE, Szabo E, Lee JJ, Dong Z, et al. Transforming cancer prevention through precision medicine and immune-oncology. Cancer Prevention Research, (2016); 9(1): 2-10.

Weiss RA. A perspective on the early days of RAS research. Cancer and Metastasis Reviews, (2020); 39(4): 1023-1028.

Ostlund A. The Translocation t (7; 12) (q36; p13) in Childhood Acute Myeloid Leukemia. (2024).

Ellsworth DL, Blackburn HL, Shriver CD, Rabizadeh S, Soon-Shiong P, Ellsworth R E. Single-cell sequencing and tumorigenesis: improved understanding of tumor evolution and metastasis. Clinical and translational medicine, (2017); 6(1): 15.

Cooper LA, Demicco EG, Saltz JH, Powell RT, Rao A, Lazar AJ. Pan Cancer insights from The Cancer Genome Atlas: the pathologist's perspective. The Journal of pathology, (2018); 244(5): 512-524.

Jarhelle E, Riise Stensland HMF, Hansen GAM, Skarsfjord S, Jonsrud C, Ingebrigtsen M, et al. Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients. Scientific reports, (2019); 9(1): 19986.

Sun K, Luo J, Guo J, Yao X, Jing X, Guo F. The PI3K/AKT/mTOR signaling pathway in osteoarthritis: a narrative review. Osteoarthritis and cartilage, (2020); 28(4): 400-409.

Morganti S, Tarantino P, Ferraro E, D’Amico P, Viale G, et al. Complexity of genome sequencing and reporting: Next generation sequencing (NGS) technologies and implementation of precision medicine in real life. Critical reviews in oncology/hematology, (2019); 133, 171-182.

Goleva E, Lyubchenko T, Kraehenbuehl L, Lacouture ME, Leung DY, Kern JA. Our current understanding of checkpoint inhibitor therapy in cancer immunotherapy. Annals of Allergy, Asthma & Immunology, (2021); 126(6): 630-638.

Klempner SJ, Fabrizio D, Bane S, Reinhart M, Peoples T, Ali SM, et al. Tumor mutational burden as a predictive biomarker for response to immune checkpoint inhibitors: a review of current evidence. The oncologist, (2020); 25(1): e147-e159.

Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell, (2018); 173(2): 321-337.

Cicirò Y, Sala A. MYB oncoproteins: emerging players and potential therapeutic targets in human cancer. Oncogenesis, (2021); 10(2): 19.

Hamid AA, Gray KP, Shaw G, MacConaill LE, Evan C, Bernard B, et al. Compound genomic alterations of TP53, PTEN, and RB1 tumor suppressors in localized and metastatic prostate cancer. European urology, (2019); 76(1): 89-97.

Alhmoud JF, Woolley JF, Al Moustafa AE, Mallei MI. DNA damage/repair management in cancers. Advances in Medical Biochemistry, Genomics, Physiology, and Pathology, (2021); 309-339.

Kontomanolis EN, Koutras A, Syllaios A, Schizas D, Mastoraki A, Garmpis N, et al. Role of oncogenes and tumor-suppressor genes in carcinogenesis: a review. Anticancer research, (2020); 40(11): 6009-6015.

Cuesta C, Arévalo-Alameda C, Castellano E. The importance of being PI3K in the RAS signaling network. Genes, (2021); 12(7): 1094.

Pertesi M, Ekdahl L, Palm A, Johnsson E, Jarvstrat L, Wihlborg A-K, et al. Essential genes shape cancer genomes through linear limitation of homozygous deletions. Communications Biology, (2019); 2(1): 262.

Lipsick J. A history of cancer research: tumor suppressor genes. Cold Spring Harbor Perspectives in Biology, (2020); 12(2): a035907.

Volkova NV, Meier B, González-Huici V, Bertolini S, Gonzalez S, Vohringer H, et al. Mutational signatures are jointly shaped by DNA damage and repair. Nature communications, (2020); 11(1): 2169.

Yoshioka KI, Kusumoto-Matsuo R, Matsuno Y, Ishiai M. Genomic instability and cancer risk associated with erroneous DNA repair. International journal of molecular sciences, (2021); 22(22): 12254.

Jiang Z, Gu Z, Lu X, Wen W. The role of dysregulated metabolism and associated genes in gastric cancer initiation and development. Translational Cancer Research, (2024); 13(7): 3854.

Fueyo R, Judd J, Feschotte C, Wysocka J. Roles of transposable elements in the regulation of mammalian transcription. Nature reviews Molecular cell biology, (2022); 23(7): 481-497.

Diederichs S, Bartsch L, Berkmann JC, Frose K, Heitmann J, Hoppe C, et al. The dark matter of the cancer genome: aberrations in regulatory elements, untranslated regions, splice sites, non‐coding RNA and synonymous mutations. EMBO molecular medicine, (2016); 8(5): 442-457.

Yang Z, Xu F, Wang H, Teschendorff AE, Xie F, He Y. Pan-cancer characterization of long non-coding RNA and DNA methylation mediated transcriptional dysregulation. EBioMedicine, (2021); 68.

Meier K, Recillas-Targa F. New insights on the role of DNA methylation from a global view. Front Biosci (Landmark Ed), (2017); 22(4): 644-668.

Zaib S, Rana N, Khan I. Histone modifications and their role in epigenetics of cancer. Current medicinal chemistry, (2022); 29(14): 2399-2411.

Liu X, Liu H. Changing expression profiles of messenger RNA, microRNA, long non-coding RNA, and circular RNA reveal the key regulators and interaction networks of competing endogenous RNA in pulmonary fibrosis. Frontiers in Genetics, (2020); 11: 558095.

Ackerman S, Horton W. Effects of environmental factors on DNA: damage and mutations. In Green Chemistry (2018); (109-128). Elsevier.

Khan AQ, Kuttikrishnan S, Siveen KS, Prabhu KS, Shanmugakonar M, Al-Naemi HA, et al. RAS-mediated oncogenic signaling pathways in human malignancies. In Seminars in cancer biology, (2019); 54,1-13.

Wang LH, Wu CF, Rajasekaran N, Shin YK. Loss of tumor suppressor gene function in human cancer: an overview. Cellular Physiology and Biochemistry, (2019); 51(6): 2647-2693.

Ray A. DNA Mutation, Repair, and Recombination. In Genetics Fundamentals Notes (2022); 433-490. Singapore: Springer Nature Singapore.

Luatti S, Baldazzi C, Marzocchi G, Ameli G, Bochicchio MT, Soverini S, et al. Cryptic BCR-ABL fusion gene as variant rearrangement in chronic myeloid leukemia: molecular cytogenetic characterization and influence on TKIs therapy. Oncotarget, (2017); 8(18): 29906.

Glenfield C, Innan H. Gene duplication and gene fusion are important drivers of tumourigenesis during cancer evolution. Genes, (2021); 12(9): 1376.

Zhang X, Sjoblom T. Targeting loss of heterozygosity: a novel paradigm for cancer therapy. Pharmaceuticals, (2021); 14(1): 57.

Postwala H, Shah Y, Parekh PS, Chorawala MR. Unveiling the genetic and epigenetic landscape of colorectal cancer: New insights into pathogenic pathways. Medical Oncology, (2023); 40(11): 334.

Pathak GA, Polimanti R, Silzer TK, Wendt FR, Chakraborty R, Phillips NR. Genetically-regulated transcriptomics & copy number variation of proctitis points to altered mitochondrial and DNA repair mechanisms in individuals of European ancestry. BMC cancer, (2020); 20: 1-13.

Asgari-Karchekani S, Aryannejad A, Mousavi SA, Shahsavarhaghighi S, Tavangar S M. The role of HER2 alterations in clinicopathological and molecular characteristics of breast cancer and HER2-targeted therapies: a comprehensive review. Medical Oncology, (2022); 39(12): 210.

Nabavi S, Zare F. Identification of copy number alterations from next-generation sequencing data. Computational Methods for Precision Oncology, (2022); 55-74.

Bhattacharya P, Patel TN. Microsatellite instability and promoter hypermethylation of DNA repair genes in hematologic malignancies: a forthcoming direction toward diagnostics. Hematology, (2018); 23(2): 77-82.

Zhang J, Yang C, Wu C, Cui W, Wang L. DNA methyltransferases in cancer: biology, paradox, aberrations, and targeted therapy. Cancers, (2020); 12(8): 2123.

Aubrey BJ, Strasser A, Kelly GL. Tumor-suppressor functions of the TP53 pathway. Cold Spring Harbor perspectives in medicine, (2016); 6(5): a026062.

Capuozzo M, Santorsola M, Bocchetti M, Perri F, Cascella M, Granata V, et al. p53: from fundamental biology to clinical applications in cancer. Biology, (2022); 11(9): 1325.

Alvarado-Ortiz E, de la Cruz-López KG, Becerril-Rico J, Sarabia-Sánchez MA, Ortiz-Sánchez E, García-Carrancá A. Mutant p53 gain-of-function: role in cancer development, progression, and therapeutic approaches. Frontiers in cell and developmental biology, (2021); 8: 607670.

Li Q, Engebrecht J. BRCA1 and BRCA2 tumor suppressor function in meiosis. Frontiers in Cell and Developmental Biology, (2021); 9: 668309.

Petrucelli N, Daly MB, Pal T. BRCA1-and BRCA2-associated hereditary breast and ovarian cancer. (2022); (5): 245-59.

Fanale D, Pivetti A, Cancelliere D, Spera A, Bono M, Fiorino A, et al. BRCA1/2 variants of unknown significance in hereditary breast and ovarian cancer (HBOC) syndrome: looking for the hidden meaning. Critical Reviews in Oncology/Hematology, (2022); 172: 103626.

Papa A, Pandolfi PP. The PTEN–PI3K axis in cancer. Biomolecules, (2019); 9(4): 153.

Chang H, Cai Z, Roberts TM. The mechanisms underlying PTEN loss in human tumors suggest potential therapeutic opportunities. Biomolecules, (2019); 9(11): 713.

Vidotto T, Melo CM, Castelli E, Koti M, Dos Reis RB, Squire JA. Emerging role of PTEN loss in evasion of the immune response to tumours. British journal of cancer, (2020); 122(12): 1732-1743.

Kolch W, Berta D, & Rosta E. Dynamic regulation of RAS and RAS signaling. Biochemical Journal, (2023); 480(1): 1-23.

Ullah R, Yin Q, Snell AH, Wan L. RAF-MEK-ERK pathway in cancer evolution and treatment. Seminars in cancer biology, (2022); 85: 123-154.

Dillon M, Lopez A, Lin E, Sales D, Perets R, Jain P. Progress on Ras/MAPK signaling research and targeting in blood and solid cancers. Cancers, (2021); 13(20): 5059.

Stefani C, Miricescu D, Stanescu-Spinu II, Nica RI, Greabu M, Totan AR, Jinga M. Growth factors, PI3K/AKT/mTOR and MAPK signaling pathways in colorectal cancer pathogenesis: where are we now? International Journal of Molecular Sciences, (2021); 22(19): 10260.

Peng Y, Wang Y, Zhou C, Mei W, Zeng C. PI3K/Akt/mTOR pathway and its role in cancer therapeutics: are we making headway? Frontiers in oncology, (2022); 12: 819128.

M Sokolowski K, Koprowski S, Kunnimalaiyaan S, Balamurugan M, Clark Gamblin T, Kunnimalaiyaan M. Potential molecular targeted therapeutics: role of PI3-K/Akt/mTOR inhibition in cancer. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), (2016); 16(1): 29-37.

Piombino C, Cortesi L, Lambertini M, Punie K, Grandi G, Toss A. Secondary prevention in hereditary breast and/or ovarian cancer syndromes other than BRCA. Journal of Oncology, (2020); 2020: 6384190.

Jackson L, Weedon MN, Green HD, Mallabar-Rimmer B, Harrison JW, Wood AR, Wright CF. Influence of family history on penetrance of hereditary cancers in a population setting. EClinicalMedicine, (2023); 64: 102159.

Schneider KA, Chittenden A, Shannon KM. Counseling about cancer: strategies for genetic counseling. John Wiley & Sons. (2023).

Samadder NJ, Riegert-Johnson D, Boardman L, Rhodes D, Wick M, Okuno S, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA oncology, (2021); 7(2): 230-237.

Assenov Y, Brocks D, Gerhäuser C. Intratumor heterogeneity in epigenetic patterns. In Seminars in cancer biology, (2018); 51: 12-21.

Turnquist C, Watson RA, Protheroe A, Verrill C, Sivakumar S. Tumor heterogeneity: does it matter? Expert Review of Anticancer Therapy, (2019); 19(10): 857-867.

Apostoli AJ, Ailles L. Clonal evolution and tumor-initiating cells: new dimensions in cancer patient treatment. Critical reviews in clinical laboratory sciences, (2016); 53(1): 40-51.

Anupriya S, Chakraborty A, Patnaik S. Clonal evolution and expansion associated with therapy resistance and relapse of colorectal cancer. Mutation Research/Reviews in Mutation Research, (2022); 790: 108445.

Malone ER, Oliva M, Sabatini PJ, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome medicine, (2020); 12: 1-19.

Vlachostergios PJ, Faltas BM. Treatment resistance in urothelial carcinoma: an evolutionary perspective. Nature reviews Clinical oncology, (2018); 15(8): 495-509.

Proietto M, Crippa M, Damiani C, Pasquale V, Sacco E, Vanoni M, et al. Tumor heterogeneity: preclinical models, emerging technologies, and future applications. Frontiers in Oncology, (2023); 13: 1164535.

Sabour L, Sabour M, Ghorbian S. Clinical applications of next-generation sequencing in cancer diagnosis. Pathology & Oncology Research, (2017); 23: 225-234.

Dhanjal DS, Chopra C, Chopra RS. Metagenomic DNA sequencing: technological advances and applications. Metagenomics: Techniques, Applications, Challenges and Opportunities, (2020); 37-53.

Qiu T, Zhi X, Ren S. Recent advance of next-generation sequencing in patients with lung cancer. Expert Review of Molecular Diagnostics, (2023); 23(11): 959-970.

Colomer R, Miranda J, Romero-Laorden N, Hornedo J, González-Cortijo L, Mouron S, et al. Usefulness and real-world outcomes of next generation sequencing testing in patients with cancer: an observational study on the impact of selection based on clinical judgement. EClinicalMedicine, (2023); 60: 102029. 60.

Ren X, Kang B, Zhang Z. Understanding tumor ecosystems by single-cell sequencing: promises and limitations. Genome biology, (2018); 19(1): 211

Lei Y, Tang R, Xu J, Wang W, Zhang B, Liu J, et al. Applications of single-cell sequencing in cancer research: progress and perspectives. Journal of hematology & oncology, (2021); 14(1): 91.

Dutta AK, Alberge JB, Sklavenitis-Pistofidis R, Lightbody ED, Getz G, Ghobrial IM. Single-cell profiling of tumour evolution in multiple myeloma-opportunities for precision medicine. Nature Reviews Clinical Oncology, (2022); 19(4): 223-236.

Lim J, Chin V, Fairfax K, Moutinho C, Suan D, Ji H, et al. Transitioning single-cell genomics into the clinic. Nature Reviews Genetics, (2023); 24(8): 573-584.

Joshi A, Kumar A, Kaushik V. Functional Genomics and Network Biology. In Advances in Bioinformatics (2024); 71-96).

Wang C, Cao Y, Yang C, Bernards R. Exploring liver cancer biology through functional genetic screens. Nature reviews Gastroenterology & hepatology, (2021); 18(10): 690-704.

Salvati A, Gigantino V, Nassa G, Mirici Cappa V, Ventola GM, Cracas DGC, et al. Global view of candidate therapeutic target genes in hormone-responsive breast cancer. International journal of molecular sciences, (2020); 21(11): 4068.

Jiang C, Meng L, Yang B, Luo X. Application of CRISPR/Cas9 gene editing technique in the study of cancer treatment. Clinical genetics, (2020); 97(1): 73-88.

Zhang G, Wang Z, Qian F, Zhao C, Sun C. Silencing of the ABCC4 gene by RNA interference reverses multidrug resistance in human gastric cancer. Oncology reports, (2015); 33(3): 1147-1154.

Przybyla L, Gilbert LA. A new era in functional genomics screens. Nature Reviews Genetics, (2022); 23(2): 89-103.

Corces MR, Granja JM, Shams S, Louie BH, Seoane JA, Zhou W, et al. The chromatin accessibility landscape of primary human cancers. Science, (2018); 362(6413): eaav1898.

Bludau I, Aebersold R. Proteomic and interactomic insights into the molecular basis of cell functional diversity. Nature Reviews Molecular Cell Biology, (2020); 21(6): 327-340.

Patil VM, Gupta SP, Masand N, Balasubramanian K. Experimental and computational models to understand protein-ligand, metal-ligand and metal-DNA interactions pertinent to targeted cancer and other therapies. European Journal of Medicinal Chemistry Reports, (2024); 100133.

Xu J, Yang P, Xue S, Sharma B, Sanchez-Martin M, Wang F, Parikh B. Translating cancer genomics into precision medicine with artificial intelligence: applications, challenges and future perspectives. Human genetics, (2019); 138(2): 109-124.

Sebastian AM, Peter D. Artificial intelligence in cancer research: trends, challenges and future directions. Life, (2022); 12(12): 1991.

Xie T, Wang Z, Zhao Q, Bai Q, Zhou X, Gu Y, Wang H. Machine learning-based analysis of MR multiparametric radiomics for the subtype classification of breast cancer. Frontiers in oncology, (2019); 9: 505.

Chen R, Yang L, Goodison S, Sun Y. Deep-learning approach to identifying cancer subtypes using high-dimensional genomic data. Bioinformatics, (2020); 36(5): 1476-1483.

Tong YF, He QE, Zhu JX, Ding EC, Song K. Multi‐omics differential gene regulatory network inference for lung adenocarcinoma tumor progression biomarker discovery. AIChE Journal, (2022); 68(4): e17574.

Ding P, Pan Y, Wang Q, Xu R. Prediction and evaluation of combination pharmacotherapy using natural language processing, machine learning and patient electronic health records. Journal of Biomedical Informatics, (2022); 133: 104164.

Chi YI, Stodola TJ, De Assuncao TM, Leverence EN, Smith BC, Volkman BF, et al. Structural bioinformatics enhances the interpretation of somatic mutations in KDM6A found in human cancers. Computational and Structural Biotechnology Journal, (2022); 20: 2200-2211.

Li X, Cai D, Huang Y, Xie Y, Shen D, Yuan Z, Wang X. Aberrant methylation in neurofunctional gene serves as a hallmark of tumorigenesis and progression in colorectal cancer. BMC cancer, (2023); 23(1): 315.




DOI: http://dx.doi.org/10.62940/als.v12i1.3334

Refbacks

  • There are currently no refbacks.